Inadequate sleep afflicts over 50 million Americans, contributing to reduced cognitive function and psychiatric disorders. How underlying sleep mechanisms go awry in sleep disorders and mental illness to disrupt cognitive function is not well understood at the molecular level. Studies suggest an intimate link between mental illness, sleep homeostasis, synaptic plasticity, and learning and memory. To address the cellular and molecular mechanisms linking these neural processes, we have been using a simple model organism, the fruit fly Drosophila. Remarkably, the fruit fly exhibits many of the core features of sleep. In fact, genetic analysis suggests that many genes involved in regulating sleep levels are conserved between Drosophila and mammals. As part of our studies to understand sleep regulation in Drosophila, we identified a role for specific neural loci, termed the mushroom bodies (MBs), in promoting restorative sleep. Of note, the MBs are also central to learning and memory. To further understand the neural and molecular basis linking sleep, arousal, and neuroplasticity, we propose to further refine MB neurons playing specific roles in sleep homeostasis. In addition, we will assess the effects of sleep deprivation on MB-dependent learning and memory and MB synapses. We will also examine the link between learning and memory genes and sleep homeostasis, including a focus on their role in mediating the effects of sleep loss on learning and memory. These studies take advantage of many aspects of the Drosophila system, including conserved mechanisms of sleep, arousal, and memory, the ability to manipulate in a targeted manner the function of neural circuits in vivo and to easily manipulate gene function to elucidate mechanisms linking sleep, memory and plasticity. Given the genetic conservation of sleep and memory pathways, these studies may shed light on underlying mechanisms of disordered sleep and its relationship to learning and memory as well as mental illness in humans. PUBLIC HEALTH RELEVANCE: Inadequate sleep afflicts millions of Americans and contributes to mental illness. Here we use a simple model to elucidate the fundamental molecular and neural mechanisms linking sleep and memory.